JPH01305955A - Production of mixture for preparation - Google Patents

Abstract

PURPOSE: To produce a mixture be preparation precisely in a short time by measuring components successively by means of an electronic differential weighting machine which has a screw conveyor and supplying the components successively into a two axes screw extruding machine, and forming plastic rod-like material. CONSTITUTION: A copolymer, e.g. stearyl alcohol and theophylline, is measured with a weighing machine that uses three microprocessors technology, supplied into a hopper of an extruding machine and extruded. The temperature of a cylinder of the extruding machine in six processes shall be 30, 60, 60, 60, 60, and 60 deg.C respectively and an extruding die is heated at 100 deg.C. The obtained rod-like material is directly compressed into rectangular tables. The new successive measurement provides more uniform weighting than that achieved by conventional non-successive weighing. Because the successive measurement is done at the preparation production site directly, all the possibility of the separation is removed.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing pharmaceutical mixtures by continuous metering of the individual components.

In the pharmaceutical industry, ingredients have traditionally been measured and mixed in batches. Because of the risk of separation in case of different bulk densities and/or flow properties, mixed batches must be kept relatively small and shunting operations and long transport distances avoided. This method is cumbersome and uneconomical, and is also not compatible with modern continuous tabletting methods that do not employ granulation (which has hitherto always been done discontinuously). Examples of such methods are direct tabletting of active substance/auxiliary substance mixtures and e.g. Dg-○S 3612212 and 3
612211 for extrusion of formulation mixtures.

There is a bias in the pharmaceutical industry against continuous metering of ingredients to produce mixtures. In the past, the required weighing accuracy (±5% of the rated value) was not achieved over a short period of time (less than 1 minute);
This prejudice was understandable since it could only be accomplished over a relatively long period of time (a few minutes). In order to be able to produce tablets whose homogeneity of composition complies with pharmacopoeial specifications by means of a common tablet press, it is necessary to meter each component in a very constant manner in seconds.

Modern electronics (the latest microprocessors)
With the further development of weighing scales using the technology (technique), the temporal metric invariance has been decisively improved. The inventors have found that these weighing scales are also suitable for use in the pharmaceutical industry. This applies in particular to the use in modern continuous tableting processes, such as the extrusion processes mentioned above.

Since the mixing is further improved in the extruder or also in the screw part of the injection molding machine, possible short-term fluctuations in the composition of the mixture are compensated for. This tabletting method is therefore particularly preferred in connection with the new metering method.

The inventors have surprisingly found that the novel continuous weighing method is not only feasible despite the biases that exist in the pharmaceutical industry, but also provides a more uniform weighing method in many cases than is achieved by traditional discontinuous methods. It was found that the results can be measured. This is because the former method, in contrast to the latter method, allows continuous weighing to take place directly at the tableting station, thereby eliminating all possibilities of separation.

Besides this decisive advantage, the new method also has important advantages in terms of space, time and personnel requirements and is more economical.

Although continuous metering of ingredients has been a long-standing practice in the plastics industry, it was not obvious to transfer this to the pharmaceutical industry. This is because there is usually no contact between the two industries, and the high requirements for metrological accuracy in the pharmaceutical industry made this type of method believed to be unsuitable for its purpose.

For example, one differential weighing scale (K-TRO
CH-5702) manufactured by N5oder AG was used. The individual components are then transferred to the extruder (often W
Model ZSK30 from Erner & Pfleidere) or directly into the hopper of an injection molding machine. The throughput of all mixtures was always in the range 2-5 ky/hr. In order to control the homogeneity of the tablet composition, three tablets each were analyzed for their active substance and auxiliary substance content. Analysis of the polymer content was omitted since it was obtained by calculation.

Parts and percentages in the examples below relate to weight.

Example 1 K value of 60% N-vinylpyrrolidone-2 (MVP) and 40% vinyl acetate ("v'ac")
13, 1932, pp. 58-64 and 71-74), 5 parts of stearyl alcohol, and 50 parts of theophylline were weighed using 6 of the above-mentioned weighing scales and added to an extruder of the above-mentioned type. The extruder cylinder consisted of 6 passes and was extruded into the hopper of
The temperature of is 3o, 60.60.60.60 and 60°C
The extrusion die was heated to 100°C. This obtained rod-shaped product is used in claims 5 and 6 of EP-A240906,
It was compressed directly into oblong tablets using the equipment described in the accompanying drawings. Analysis of these tablets has the following results.

Active substance: 49.9 50.2 49.
7% stearyl alcohol: 5. IO4,925,03
% Example 2 50 parts of the copolymer of Example 1 and 50 parts of theophylline were mixed and extruded in a twin screw extruder as in Example 1 and then similarly compressed into oblong tablets. The temperature of the passage through the extruder is 30.60.60.60.90 and 12
It was 0°C. The extrusion die was also at 120°C.

Analysis of active substance content: 49.3.50.1 and 50.5
% Example 3 Obtained from NVP 60% and Vac 40%, K value 60
Example 1: 47.5 parts of a copolymer having 2.5 parts of crosslinked polyvinylpyrrolidone (pvp) as tablet disintegrant and 50 parts of theophylline in a twin screw extruder.
Mixed and extruded in the same manner as above, and then molded in the same manner as (.5
The pass temperature for each pass was 120°C, and the extrusion die temperature was 130°C.

Analysis of active substance content: 50.6.50.1 and 498%
Example 4 Obtained from 1αP 30% and Vac 70%, K value 52
50 parts of the copolymer having the formula and 50 parts of theophylline were mixed and extruded in a twin screw extruder in the same manner as in Example 1, and compressed into tablets.

The temperatures for the 5 passes were 30.60.100.100 and 120°C. The extrusion die was heated to 120°C as well.

Analysis of active substance content: 50.8.499 and 496% Examples 5 to 8 A mixture of 50% IJVP homopolymer and 50% theophylline having the values shown in the table below, respectively, was prepared in Example 1.
They were weighed and fed into a single screw extruder in the same manner as above, melted and extruded at the temperatures shown in the table, and compressed into tablets in the same manner as in Example 1. Six tablets each were then analyzed for active substance content.

5 12 115125135135135 145
51.049.449.66 17 125 1251
35145145 155 49.950,8 49.
27 25 145155165175175 175
50.549.1 50.78 30 150 16
0160170180 180 49.1 50.5
50.8 Example 9 40 parts of a copolymer with a value of 30 from NVP 6 Q% and Vac 40%, 10 parts of polyhydroxyethyl methacrylate and 50 parts of theophylline were processed analogously to Example 1. The temperature of the passage is 70.80.80.80
．． The temperature was 80°C and the extrusion die was 90°C.

Active substance content: 50.2.50.4 and 49.8 Example 10 Commercially available 80% hydrolyzed polyvinyl acetate 50
and 50 parts of theophylline were processed in the same manner as in Example 1. The temperature of the passage is 100.100.110.120,
i 3a 'c, and the extrusion die temperature was 150°C.

Theophylline content = 49.1.50.4 and 498% Example 11 50 parts of polyhydroxyethyl methacrylate having a value of 30 and 50 parts of theophylline were processed analogously to Example 1. The temperature of the passage is 120.130.150.160
．． The extrusion die temperature was 170°C.

Theophylline content: 498.50.4 and 50.1% Examples 12-14 36 parts of copolymer with a value of 60 from MVP 60% and Vac 40%, 4 parts of stearyl alcohol, 40 parts of theophylline and 20 parts each Example 12: Starch Example 13: Lactose Example 14: Shiyotang was metered and fed into a 6 pass twin screw extruder as in Example 1, extruded and compressed similarly. It was made into tablets. The temperature of the passage is 90.100.110.120,
120, the temperature is 130℃, and the temperature of the extrusion die is 1
The temperature was 65°C. Theophylline content was as follows.

Example 12: 50.0.50.3.50.1% Example 1
3:50.4.499.496% Example 14:49.9
．． 50.3.497% Examples 15-17 50 parts of the copolymer of Examples 12-14 and 50 parts of verapamil
A portion was molded into tablets in the same manner as in Examples 12-14.

Verapamil content: Example 15: 49.8.496.50.0% Example 16
: 50.1.498.50.4% Example 17: 50.3
．． 50.5.49.9% The following examples were carried out in a similar manner to the previous examples. The processing conditions and the determined contents of active substances and monomer auxiliaries are shown in the following figure.

75AI/61.5/29.5/'9.0404550
5076 Methu Mound Roll A Starch
40/'45/'15 60 70 80 8°77
# A 〃40/
35/25 55 60 65 7078 Anipamil A Milk 1.1j 32/43. ,
'25 55 60 70 8079
A Cellulose 32//'6t2
/6.8 55 60 70 808〇
8 Lactose 32/'34.4/i3.6
55 60 70 80 IN
A Starch 32//''544/16.655
60 70 a.

82 Caffeine powder A:;tA5
0/45/'5 65 75 90 9085
A-50/”
'50 65 75 90 9084 Caffeine granules A 3LA 50/45
/'5 65 70 70 7585
A -50/'50 65
70 70 7550 50 50 61
．． 4 60.9 61.9 8,93
9. [l14 8.9880 80 80
40.4 39.8 40.070 70
70 40.2 40.1 69.77
0 70 65 3+, 8 32.0
32265 65 60' 32,0
31.9 32:265 65 60
523 322 51.865 65 60
32.0 3+, 8 32.090
90 100 50.4 50.2 50
．． 3 5. G6 4.97 4.9590
90 +00 50.2 50.3
49.875 90 80 50.0
49.5 49.6 4,95 4.98
5.0375 90 80 50.2
50.5 49.8 A = copolymer of 60% by weight MVP and 40% by weight vinyl acetate, K value approx. 63 8 = PVP, value 12 C = PVP, value 17 D = Mowio, l 30-92 (92% Hydrolyzed polyvinyl alcohol) F, = Mowiol 4-80 (80% hydrolyzed polyvinyl alcohol) F = MVP, copolymer from vinyl acetate and hydroxypropyl acrylate in a weight ratio of 30:40:30, K value Approximately 18 G - Cellulose acetate H - Cellulose acetate 7 Crate 1 = Vinyl acetate/crotonic acid copolymer, K value approximately 60 StA = Stearyl alcohol S tHj = = = Stearic acid! , Ig31. -Magnesium stearate Example 86 50 parts of a copolymer with a value of 30 from NVP 60% and Vac 40% and 50 parts of theophylline are metered continuously into the hopper of an injection molding machine and heated to 120°C. The tablets were processed into oblong tablets with a length of 1 c'In. Active substance content: 50.8.494 and 50.5% Example 87 47.5 parts of the copolymer of Example 86, 2.5 parts of stearyl alcohol and 50 parts of theophylline were weighed continuously into an injection molding machine. The tablets were processed into 6 sugar-coated tablets at 100°C and left at room temperature. Theophylline content: 49. D, 50
．． 6 and 50,9%.

Stearyl alcohol content: 2.56, 2.49 and 2,44%.

Example 88.

, valacetamol 25%, and DE-A364263
75% of PVP (K value 12) prepared in water with an organic peroxide as an initiator according to No. 3 was metered continuously into the feed port of the injection molding machine and the extrusion die temperature was adjusted to 130°C.
Six sugar-coated tablets were molded at °C.

Active substance content: 24.7.25, 2 and 24.9% Examples 89 and 90 Example 88 was repeated using phenytoin or bensicaine as active substance.

Active substance content:

Claims (1)

[Claims] 1. A method for producing a pharmaceutical mixture, characterized by continuously measuring and molding the ingredients. 2. Process according to claim 1, characterized in that the components are metered continuously into an extruder and the extruded plastic rods are shaped. 3. Process according to claim 1, characterized in that the components are metered continuously into a twin-screw extruder and the extruded plastic rods are shaped. 4. Process according to claim 1, characterized in that the components are continuously metered into a hopper of an injection molding machine and injection molded. 5. The method according to any one of claims 1 to 4, characterized in that the components are continuously weighed by an electronic differential weighing scale having a screw conveyor. 6. Process according to claim 5, characterized in that the components are weighed continuously by means of an electronic differential weighing scale with a scraping self-purifying twin screw as conveyor element. 7. The method according to any one of claims 1 to 6, characterized in that the individual amounts measured per hour are 50 g or more.